1. Field of the Invention
This invention relates to a hepatic fibrosis inhibitor.
2. Description of the Related Art
Hepatic fibrosis is a condition in which production of fibrous tissues referred to as extracellular matrix formed of collagen and complex carbohydrate is accelerated, consequently to be gradually accumulated with progression of inflammation in the course of repairing necrotic hepatocytes necrotized by viral hepatitis, alcohol liver diseases, autoimmune hepatic disorders, metabolic hepatic disorders or the like.
In early stages of inflammation, the hyperplastic extracellular matrix is eventually absorbed and cured without being accumulated, but production of the matrix in a case of chronic hepatitis maintaining its inflammatory conditions exceeds decomposition and absorption of the matrix to continue accumulation of the fibrous tissues, consequently to repeat a vicious circle that the hepatic parenchymal cells pressured by the accumulated fibrous tissues are damaged, resulting in accelerated production of the fibrous tissues, and eventually lead to hepatic cirrhosis in which the liver becomes hardened and malfunctions due to the fibrous tissues.
The hepatic cirrhosis is difficult to cure, and, in many cases, the liver cirrhosis progresses to liver cancer. Particularly, hepatitis C which is possibly spread to others by virus-tainted blood products and has become a serious social issue progresses from chronic hepatitis to the liver cancer via the hepatic cirrhosis at high rates. Hence, treatment to suppress the hepatic inflammation and fibrosis is important, but at present, there is a paucity of therapeutic drugs having few side-effects and high curative effect.
Recently, it has been thought that hepatic stellate cells and TGF-β undertake an important role in progression of hepatic fibrosis. The hepatic stellate cells are activated by cytokine released by the inflammatory cells such as macrophages to actively produce the extracellular matrix including type I collagen. Meanwhile, TGF-β was identified as a cytokine for stimulating genetic transformation and proliferation of normal fibroblasts and has effects for stimulating the proliferation of the activated stellate cells and the production of the extracellular matrix and antiproliferative activity of the hepatic parenchymal cells. Thus, the development of curative drugs for suppressing the effect of TGF-β or excess production of TGF-β has been advanced in order for controlling the hepatic fibrosis.
Based on this viewpoint, as examples of an inhibitor for inhibiting hepatic fibrosis due to an anti-TGF-β action or TGF-β production inhibiting action, there have been studied an integrin inactivator in Patent Literature 1, an ALK5 inhibitor in Patent Literature 2, and an anti-TGF-β receptor peptide in Patent Literature 3. Further, as one example, Patent Literature 4 discloses that an iNOS-activity inhibitor of a specific configuration having an action of inhibiting NO-production shows suppressant actions on the production of TGF-β and hepatic fibrosis.
A hydroquinone derivative represented by the following chemical formula (1) has potent antioxidant action and NO-production inhibiting action. The inventors of the present invention have devised an antioxidant agent containing such a compound as an active constituent (Patent Literature 5), a curative drug for refractory inflammatory affection such as arthritis rheumatoides and nonspecific imflammatory bowel diseases (Patent Literature 6), a carcinogenic inhibitor (Patent Literature 7), and a therapeutic agent for arterial sclerosis (Patent Literature 8).

Patent Literature 9 provided by the inventors of the present invention discloses a therapeutic composition for treatment of liver disorder containing the present compound as an active constituent. This literature concretely describes with respect to the effectiveness of the composition against alpha-naphthyl isothiocyanate (ANIT)-induced acute hepatic damage in mice on the basis of pharmacological examples and clarifies high safety of the composition through safety testing.
Patent Literature 1: Japanese Published Unexamined Pub. No. 2002-530431
Patent Literature 2: Japanese Published Unexamined Appln. No. 2005-343889
Patent Literature 3: Japanese Published Unexamined Appln. No. 2007-186519
Patent Literature 4: Japanese Published Unexamined Appln. No. 2005-41837
Patent Literature 5: Japanese Published Unexamined Appln. HEI 5-301836
Patent Literature 6: Japanese Published Unexamined Appln. No. 2004-352661
Patent Literature 7: Japanese Published Unexamined Appln. HEI 6-100441
Patent Literature 8: Japanese Published Unexamined Appln. No. 2002-241366
Patent Literature 9: Japanese Published Unexamined Appln. HEI 8-67627
However, each of the compounds mentioned in Patent Literatures 1-4 is still being studied as a hepatic fibrosis inhibitor. There has not yet been found an effective drug for restraining the progression of hepatic fibrosis and hepatic cirrhosis. Also, Patent Literatures 5-9 do not mention that the compound represented by the aforementioned chemical formula (1) exerts a suppressant action for suppressing hepatic fibrosis.
In the meantime, the inventors of this invention have found that the antibody valency of Naofen (GenBank Accession Number EF613262) which is in vivo protein newly found as an anti-verotoxin 2 (VT2) antibody reactive substance increases in an induction model of hepatic cirrhosis and hepatic fibrosis caused by carbon tetrachloride in rats. In the light of the fact that the increase of the antibody valency occurs previous to the production of TGF-β1 and the production of collagen, it has been found that the Naofen affects the hepatic cirrhosis and hepatic fibrosis earlier than the production of TGF-β1.
Hence, the inventors of this invention have earnestly carried their investigation forward to find a substance with suppressive activity for suppressing the increase of antibody valency of intrahepatic Naofen in the aforementioned model as a substance having a suppressant action on hepatic fibrosis. Further, the inventors have continued the research in anticipation of the suppressant action of Naofen on the ground that the hydroquinone derivative represented by the foregoing general formula (1) has the suppressant action on hepatic damage.
In the meanwhile, the causal relation among the hepatic fibrosis, the production of TGF-β1 and inducible NO synthase enzyme-derived NO has not yet fully manifested, and also, it is not clarified whether the NO-production inhibiting action works as the suppressant action on hepatic fibrosis as well. The inventors of this invention have further pursued the research for demonstrating the prediction about the hydroquinone derivative represented by the aforementioned chemical formula (1) has the TGF-β production inhibiting action as well as the iNOS-activity inhibitor and the suppressant action on hepatic fibrosis.
As a result, the present invention has been achieved by finding that the aforementioned compound which has effects for inhibiting the expression of Naofen and further the expression of TGF-β1 mRNA, thus to inhibit hepatic fibrosis is useful as an inhibitor for suppressing hepatic fibrosis.